Palladium-catalyzed C-H activation/intramolecular amination reaction: A new route to 3-aryl/alkylindazoles

Article abstract of DOI:10.1021/ol0711117

A method for the catalytic C-H activation of hydrazone compounds followed by intramolecular amination is described. It requires the use of a catalytic amount of Pd(OAc)₂ in the presence of Cu(OAc)₂ and AgOCOCF₃, which effi

Full text of DOI:10.1021/ol0711117

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2931-2934
Palladium-Catalyzed C−H Activation/
Intramolecular Amination Reaction:
A New Route to 3-Aryl/Alkylindazoles
Kiyofumi Inamoto,* Tadataka Saito, Mika Katsuno, Takao Sakamoto, and
Kou Hiroya*
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity, 6-3, Aoba, Aramaki,
Aoba-ku, Sendai 980-8578, Japan
inamoto@mail.pharm.tohoku.ac.jp
Received May 14, 2007
ABSTRACT
A method for the catalytic C−H activation of hydrazone compounds followed by intramolecular amination is described. It requires the use of
a catalytic amount of Pd(OAc)2 in the presence of Cu(OAc)2 and AgOCOCF3, which efficiently effects the cyclization to afford variously substituted
indazoles. The reactions proceed under relatively mild conditions and thus tolerate a variety of functional groups, including alkoxycarbonyl
and cyano groups and halogen atoms.
Inter- and intramolecular carbon-nitrogen bond formation
is important in both academic and industrial chemistry, due
to the high prevalence of nitrogen-atom-containing biologi-
cally active compounds and pharmaceuticals. In particular,
Pd- or Cu-catalyzed amination reactions of aryl halides or
pseudohalides have been widely used to construct such
compounds, and highly active catalyst systems have been
reported.1,2 In these cases, however, aryl electrophiles must
possess a halide or pseudohalide moiety, which can limit
their utility. On the other hand, notable advances in which
catalytic C-H bond activation is accomplished by using Ru,3
Rh,4 and Pd5 followed by C-N bond formation have been
described recently. Buchwald reported Pd(II)-catalyzed C-H
activation/intramolecular amidation for carbazole synthesis
in 2005.5a More recently, Che disclosed that it was possible
to activate sp3 as well as sp2 C-H bonds in the presence of
Pd(OAc)2, followed by intermolecular amidation.5b Here we
describe a new approach to the synthesis of 3-aryl/alkylin-
dazoles,6 which are important pharmacophores, via Pd-
catalyzed C-H amination reactions of hydrazone compounds
(1) For selected recent reports on Pd-catalyzed amination of aryl halides,
see: (a) Strieter, E. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45,
925-928. (b) Kitagawa, O.; Yoshikawa, M.; Tanabe, H.; Morita, T.;
Takahashi, M.; Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc. 2006, 128,
12923-12931. (c) Dai, Q.; Gao, W.; Liu, D.; Kapes, L. M.; Zhang, X. J.
Org. Chem. 2006, 71, 3928-3934. (d) Bedford, R. B.; Betham, M. J. Org.
Chem. 2006, 71, 9403-9410. (e) Olof, J. Synthesis 2006, 2585-2589. (f)
Shashank, S.; Hartwig, J. F. Organometallics 2007, 26, 340-351. (g) Chen,
G.; Lam, W. H.; Fok, W. S.; Lee, H. W.; Kwong, F. Y. Chem. Asian J.
2007, 2, 306-313.
(2) For selected recent reports on Cu-catalyzed amination of aryl halides,
see: (a) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742-
8743. (b) Wolf, C.; Liu, S.; Mei, X.; August, A. T.; Casimir, M. D. J. Org.
Chem. 2006, 71, 3270-3273. (c) Zhu, D.; Wang, R.; Mao, J.; Xu, L.; Wu,
F.; Wan, B. J. Mol. Catal. A 2006, 256, 256-260. (d) Yeh, V. S. C.;
Wiedeman, P. E. Tetrahedron Lett. 2006, 47, 6011-6016.
(3) For recent reports, see: (a) Leung, S. K.-Y.; Tui, W.-M.; Huang,
J.-S.; Che, C.-M.; Liang, J.-L.; Zhu, N. J. Am. Chem. Soc. 2005, 127,
16629-16640. (b) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Yu, W.-Y.; Che,
C.-M. Angew. Chem., Int. Ed. 2002, 41, 3465-3468. (c) Liang, J.-L.; Huang,
J.-S.; Yu, X.-Q.; Zhu, N.; Che, C.-M. Chem.sEur. J. 2002, 8, 1563-1572.
(4) For recent reports, see: (a) Espino, C. G.; Fiori, K. W.; Kim, M.;
Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378-15379. (b) Guthikonda,
K.; Du Bois, J. J. Am. Chem. Soc. 2002, 124, 13672-13673. (c) Espino,
C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598-600.
(5) (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560-14561. (b) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am.
Chem. Soc. 2006, 128, 9048-9049.
(6) (a) Inamoto, K.; Katsuno, M.; Yoshino, T.; Arai, Y.; Hiroya, K.;
Sakamoto, T. Tetrahedron 2007, 63, 2695-2711. (b) Inamoto, K.; Katsuno,
M.; Yoshino, T.; Suzuki, I.; Hiroya, K.; Sakamoto, T. Chem. Lett. 2004,
1026-1027.
10.1021/ol0711117 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/27/2007

Table 1. Optimization of Reaction Conditionsa
Scheme 1. C-H Amination for the Synthesis of Indazoles
Pd(OAc)2 Cu(OAc)2
additive
(mol %)
yieldb,c SMd
entry (mol %)
(mol %)
(%)
(%)
1e
2
3
4
5
6
7
8
9
50
30
20
20
20
20
20
20
20
20
10
10
20
100
100
100
200
100
100
100
100
100
100
100
100
0
-
-
-
-
95 (95)
85 (85)
83 (58)
85 (58)
81 (65)
8 (2)
81 (43)
94 (62)
90 (90)
94 (94)
80 (33)
0
0
(Scheme 1). This method features the use of novel combina-
tions such as Pd(OAc)2/Cu(OAc)2/AgOCOCF3, which suc-
cessfully effect catalytic C-H activation7 followed by
amination to give the cyclized products. Indeed, compared
with the previously reported methods, this cyclization
proceeds under milder reaction conditions (50 °C) and hence
tolerates various functional groups such as alkoxycarbonyl
and cyano groups and halogen atoms.
30
32
20
29
47
34
0
0
59
0
MS 4Åf
LiBr (30)
Bu4NBr (20)
AgOAc (200)
AgBF4 (200)
AgOCOCF3 (200)
AgOCOCF3 (100)
10
11
12
13
Our investigation began by examining the conversion of
benzophenone tosylhydrazone 1 to the corresponding inda-
zole 2 (Table 1). From systematic screenings of a range of
palladium sources, oxidants, and solvents,8 we found that
the C-H amination reaction would occur in DMSO at 50
°C in the presence of Pd(OAc)2 and Cu(OAc)2 and provide
indazole 2 in high yield (85%, entry 2). In this system,
however, a reduced amount of catalyst loading led to a
significant drop in conversion (entry 2 vs 3). Thus, we next
evaluated the effects of added compounds. We were pleased
to find that some Ag salts, especially AgOCOCF3, consider-
ably enhanced the process (entries 10-12). Finally, we
determined the optimal condition as 10 mol % of Pd(OAc)2,
1 equiv of Cu(OAc)2, and 2 equiv of AgOCOCF3 in DMSO
(0.05 M) (entry 12).9
AgOCOCF3 (200) 90 (90)
AgOCOCF3 (200) 81 (26)
68
a Reagents: hydrazone 1 (50 mg), Pd(OAc)2 (above), Cu(OAc)2 (above),
additive (above), and DMSO (0.05 M). b Based on consumed starting
material. c Isolated yield in parenthesis. d SM ) starting material. e 120 °C.
f 100 mg.
electron-donating methoxy groups at the meta position
greatly accelerated this process, providing the product in
quantitative yield with high regioselectivity, with the cy-
Table 2. Cyclization of Hydrazones with Various Substituents
on the Benzene Ringa
The catalytic activity of this system was next evaluated
in the cyclization of substrates with various substituents on
the benzene ring (3a-3f in Table 2). Whereas the reaction
of 3a, bearing two para-methoxy groups, was sluggish (entry
1), 3b, with two para-methyl groups, gave the desired
indazole with good conversion and yield (entry 2). Notably,
(7) For selected recent reports on Pd(II)-catalyzed C-H bond activation,
see: (a) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8,
1141-1144. (b) Hull, K. L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem.
Soc. 2006, 128, 14047-14049. (c) Hull, K. L.; Lanni, E. L.; Sanford, M.
S. J. Am. Chem. Soc. 2006, 128, 7134-7135. (d) Giri, R.; Maugel, N.; Li,
J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am.
Chem. Soc. 2007, 129, 3510-3511. (e) Chen, X.; Goodhue, C. E.; Yu,
J.-Q. J. Am. Chem. Soc. 2006, 128, 12634-12635. (f) Wang, X.; Gribkov,
D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476-1479. (g) Ackermann, L.;
Althammer, A. Angew. Chem., Int. Ed. 2007, 46, 1627-1629. (h) Chiong,
H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449-1451. (i) Lazareva, A.;
Daugulis, O. Org. Lett. 2006, 8, 5211-5213. (j) Shabashov, D.; Daugulis,
O. Org. Lett. 2006, 8, 4947-4949. (k) Rudolph, A.; Rackelmann, N.;
Lautens, M. Angew. Chem., Int. Ed. 2007, 46, 1485-1488. (l) Ueura, K.;
Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407-1409. (m) Nakano, M.; Satoh,
T.; Miura, M. J. Org. Chem. 2006, 71, 8309-8311. (n) Orito, K.; Miyazawa,
M.; Nakamura, T.; Horibata, A.; Ushito, H.; Nagasaki, H.; Yuguchi, M.;
Yamashita, S.; Yamazaki, T.; Tokuda, M. J. Org. Chem. 2006, 71, 5951-
5958. (o) Zhao, J.; Yue, D.; Campo, M. A.; Larock, R. C. J. Am. Chem.
Soc. 2007, 129, 5288-5295. (p) Liu, G.; Stahl, S. S. J. Am. Chem. Soc.
2007, 129, 6328-6335.
a Reagents: hydrazone 3 (50 mg), Pd(OAc)2 (10 mol %), Cu(OAc)2 (1
equiv), AgOCOCF3 (2 equiv), and DMSO (0.05 M), 50 °C, 10-24 h.
b Based on consumed starting material. c Isolated yield in parenthesis. d SM
) starting material. e Single isomer, geometry could not been determined.
(8) For details, see Supporting Information.
(9) (a) Use of Pd(OCOCF3)2 instead of Pd(OAc)2 in the absence of
AgOCOCF3 gave a lower yield and conversion; see Supporting Information.
(b) More concentrated conditions such as 0.1 M led to significant decreases
in yields; see Supporting Information.
2932
Org. Lett., Vol. 9, No. 15, 2007

zophenone tosylhydrazones (3g-3o, Table 3). From the
reactions of hydrazones with various substituents at the meta
position (3g-3l), the corresponding indazoles were obtained
in generally good yield (entries 1-6). Interestingly, the
regioselectivity of these reactions was highly dependent on
the character of the substituent on the arene. For example,
the reactions of substrate with electron-donating groups, such
as hydroxy and amino groups, proceeded exclusively on the
A1 benzene ring (entries 1 and 2), while substrates that had
an electron-withdrawing group on the arene preferentially
afforded the products that resulted from the cyclization at
the nonsubstituted A2 benzene ring (entries 4-6). This means
that an electron-donating group at the 3-position could
accelerate the aromatic electrophilic substitution, leading to
the regioselective cyclization. On the other hand, cyclization
occurred preferentially on the A2 benzene ring in the
reactions of para-substituted hydrazones with both electron-
donating and -withdrawing groups (entries 7-9). Further-
more, a comparison of the results between entries 8 and 9
provided insight into the reaction mechanism: when the
reactions of 3n of different isomer ratios (E:Z ) 1:0.04 vs
0.31:1) were carried out independently, the desired indazole
4n was obtained in similar conversions and yields from the
two reactions, along with the starting material in similar E
and Z ratios (E:Z ) 1:1 from entry 8, 1:1.3 from entry 9).
These results suggest that the isomerization of hydrazones
can occur easily under the conditions used in this system.
In addition, a substrate with an ortho-bromo group gave the
dehalogenated cyclized product exclusively (entry 10).
Table 3. Cyclization of R-Phenyl R-Substituted
Phenylhydrazonesa
a Reagents: hydrazone 3 (50 mg), Pd(OAc)2 (10 mol %), Cu(OAc)2 (1
equiv), AgOCOCF3 (2 equiv), and DMSO (0.05 M), 50 °C, 12-24 h.
b Based on consumed starting material. c Isolated yield in parenthesis. d SM
) starting material. e 80 °C. f A mixture of E-/Z-isomers (1.3:1-3:1,
determined by 1H NMR or HPLC), geometries could not been determined.
g Single isomer, geometry could not been determined. h Regioisomeric
products formed could be separated from one another except 4i.
In a further attempt to broaden the scope of the above
system, we found that 3-alkylindazole 6 could also be
prepared from the corresponding hydrazone 5 in good yield
(Scheme 2).
clization occurring at the less hindered 6-position of 3c (entry
3). Furthermore, when the substrate had two different
substituents at the meta position (-OMe and others, 3d-
3f), C-H activation occurred exclusively at the 6-position
on the more electron-rich (methoxy group substituted)
benzene ring (entries 4-6), suggesting that this cyclization
may be controlled by both steric and electronic factors on
the arene.
This C-H amination most likely proceeds via the reaction
pathway depicted in Figure 1.10 Nitrogen-atom-directed
association of Pd(II) followed by C-H bond activation may
occur first, resulting in the formation of a six-membered
palladacycle. Reductive elimination then affords 3-arylin-
dazole and Pd(0). Cu(OAc)2 and AgOCOCF3 may be
We next examined the scope of the Pd(OAc)2/Cu(OAc)2/
AgOCOCF3 system with a series of monosubstituted ben-
Figure 1. Postulated reaction mechanism.
Org. Lett., Vol. 9, No. 15, 2007
2933

understand the precise reaction mechanism as well as to
expand the range of substrates are underway in our labora-
tory.
Scheme 2. Synthesis of 3-Alkylindazole
Supporting Information Available: Detailed experi-
mental procedures and spectroscopic and analytical data for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0711117
involved in the reoxidation step of Pd(0), although the precise
reaction mechanism for this step remains to be elucidated.11,12
In summary, we have developed a novel protocol for
indazole synthesis via direct C-H activation followed by
intramolecular amination in the presence of a Pd(II) catalyst.
The reactions proceed under relatively mild reaction condi-
tions, allowing high functional group tolerance. Efforts to
(10) Buchwald proposed a similar reaction mechanism for the Pd(II)-
catalyzed C-H activation process; see ref 5a.
(11) Interestingly, the use of Cu(OAc)2 or AgOCOCF3 alone as an
oxidant led to decreased conversions and yields. For details, see Supporting
Information.
(12) Very recently, a similar Cu(II)/Ag(I) system was used for the
reoxidation of Pd(0) to Pd(II) in C-H arylation of acetanilides; see: Yang,
S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066-6067.
2934
Org. Lett., Vol. 9, No. 15, 2007